There is a pressing need for new therapeutics and preventatives for HIV/AIDS. Although currently available antiretroviral drugs can control viral replication and delay the onset of immune failure in most HIV-infected individuals, they do not completely eliminate the virus. Furthermore, there are no effective biomedical measures to prevent new infections, which continue to accelerate world-wide. We are using molecular biology, protein engineering, and rational drug design to develop new therapeutics and preventatives for HIV. One project is to develop a strategy that will reduce the size of the latent reservoir of HIV that is responsible for viral persistence. This is accomplished by using synthetic analogues of diacylglycerol or histone deacetylase inhibitors to induce the expression of latent infectious virus, then killing the induced cells with targeted toxins that bind to the viral envelope protein. A second project is to develop live microbes that can prevent new HIV infections by secreting anti-HIV peptides onto the mucosal surfaces where sexual transmission of HIV occurs. We have demonstrated the feasibility of this live microbicide approach by genetically engineering commensal strains of both rectal and vaginal bacteria to secrete high levels of HIV fusion inhibitor proteins both in vitro and in vivo. This novel live microbial microbicide is currently being tested in nonhuman primates. During the course of this research, we also discovered that one particular type of chemical microbicide, cellulose sulfate, actually increases HIV infection rates, empasizing the need for more through pre-clinical evaluation of such substances. A new project involves the development of novel high definition real time video methods to monitoring HIV infection and growth in tissue explants. These will provide a novel assay system for the efficacy of microbicides.